5. Risk Groups – Colorectal Cancer
Persons who due to a special predisposition have a higher risk for the development of colorectal cancer in comparison to the normal population, usually belong to one of three defined risk groups:
- Persons who due to a special predisposition have a higher risk for the development of colorectal cancer in comparison to the normal population, usually beloPeople with a familial increased risk (genetic reasons not yet known) for a colorectal cancer
- Proven or possible carriers for hereditary colorectal cancer
- Persons at risk due to inflammatory bowel disease
5.1 Sporadic Colorectal Cancer
5.1.1 Risk Groups
5.1.1.1 Relatives of Patients with Colorectal Cancer
Background
About 20-30% of CRC cases occur as "familial cumulation" i.e. a cumulation of cancer can be observed within a family, although no specific genetic cause can be identified. In these cases the term "familial colorectal cancer" is used [184]. For first degree relatives (parents, siblings, children), the average CRC risk is increased by a factor of two to three. A further, three to four-fold risk increase is present if the index patient developed colorectal cancer before age 60 and/or more than one first degree relative had CRC [185][186][187][188][189][190][191][192][193][194][195][196][197]. In this group, there are also cases of undiscovered hereditary colon cancer (e. g. HNPCC; see below). The risk is higher for colon cancer than for rectal cancer (relative risk 2.4 vs.1.9). For first-degree relatives of affected patients, the CRC risk can be divided further. The risk for siblings is about 2.5-times higher than for the children. If the index patient developed colorectal cancer after age 60, the CRC risk for first degree relatives is only slightly increased [186][198].
Second degree relatives (grandparents, siblings of the parents, grandchildren) of patients with colorectal cancer have a slightly increased cancer risk (RR 1.5); however, this has not been adequately studied and verified in clinical practice [185][188][189][199][200]. Third degree relatives of patients with colorectal cancer do not seem to be at an increased cancer risk.
5.1.1.2 Relatives of Patients with Colorectal Adenomas
Background
The risk for these relatives to develop colorectal cancer is on average about two-fold higher compared to the general population [186][189][201][202][203][204]; there is an 80% higher risk for parents and siblings of adenoma patients in comparison to their spouses [201]. Again the risk level depends on the age of the index patient: If this person is younger than 60, the average risk is only slightly increased. If the person is younger than 50, the risk is increased about 4.4 fold [202]. If the index patient is older than 60, the colorectal cancer risk is not significantly increased.
Due to the data available, there is no evidence that the relatives of patients with hyperplastic polyps have an increased risk of developing a colorectal cancer. An exception is the extremely rare hyperplastic polyposis syndrome.
5.1.1.3 Patients with Colorectal Adenomas
Background
In general, the removal of small singular adenomas results in a reduced risk of up to 90% to develop metachronous colorectal cancer [205][206][207][208]. This reflects the preventive value of colonoscopies in the context of the adenoma-carcinoma sequence. The purpose of control examinations is especially to discover missed or metachronous adenomas.
Adenomas larger than 1 cm are associated with a four-fold increase in cancer risk [189][208][209][210][211][212][213][214][215]. In addition, multiple adenomas are also associated with an increased risk (4- 6fold) of developing a metachronous cancer [189][208][210][211][213][214]. On the one hand, this increased risk is likely due to a higher individual disposition and, on the other hand, to an increased rate of missed polyps during the initial colonoscopy. In case of detection of ≥3 polyps during colonoscopy there is a significantly higher chance of missed polyps [112][216].
An increased familial colon cancer risk is identified by medical history. However, there is no mandatory documentation of the family history or their repetition in intervals. The use of standardized questionnaires may be useful to improve the identification of persons with increased risk.
- Consensus
- Strong consensus
Background
A risk assessment is usually performed by the physician using the medical history. One possibility to integrate the risk assessment in medical care would be the use of standardized questionnaires in the general practitioner's office at the age of 35 years as part of the check-up exam that is offered at this time.
f the patient does not come to the practice at the abovementioned time, the questioning can be done later by integrating it as a memo into the practice software. A corresponding concept is currently being considered in the Joint Federal Committee.
Other relevant sites are gynecologic practices, because regular visits are recommended for gynecologic cancer screening as well as gastroenterologic practices.
Furthermore, a number of questionnaires are freely accessable via the internet:
- http://www.onkozert.de/hinweise_zertifizierung_genetische_beratung.html
- http://www.netzwerk-gegen-darmkrebs.de/index.php?id=103
- http://www.felix-burda-stiftung.de/darmkrebs/frageboegen/index.php?f=2
- http://www.lebensblicke.de/darmkrebs/
- http://www.ilco.de/darmkrebs/erblicher-darmkrebs.html
- http://www.krebsrisikotest.de/
The questionnaire used by the "Netzwerk gegen Darmkrebs“ has been evaluated [217]. There are currently no data on the other questionnaires.
5.1.2 Primary Prevention
5.1.3 Screening Tests
5.1.3.1 First-degree Relatives of Patients with Colorectal Cancer
First-degree relatives of patients with colorectal cancer should undergo a complete colonoscopy starting at an age 10 years before the age at which the index patient was diagnosed with CRC. However, this should be done at the latest at the age of 40- 45 years. Colonoscopies should be repeated at least every 10 years if initially the colon was free of polyps.
- Consensus
- Strong consensus
Background
The risk of a first-degree relative of a CRC patient to develop a colorectal cancer is increased especially if the index patient's age at diagnosis is less than 50 [189][191][198][200][222][223][224][225][226][227].
The recommendation follows the American guideline recommendation [228]. It recommends a colonoscopy at the age of 40 years if a first-degree relative developed CRC before the age of 60 or if two or more first-degree relatives had CRC (independent of the age at diagnosis).
There is no data on the maximum examination interval for this group; at this time it appears probable that an interval of 10 years is usually adequate. However, the 10-year interval should not be exceeded. The American guideline recommends a 5-year interval.
First-degree relatives from patients' families who fulfill the Amsterdam Criteria and who also have microsatellite stability (MSS) in their cancer should be closely monitored:
If at least two independent cancer from a family show MSS, colonoscopies should be performed in 3-5 year intervals from age 25.
If only one cancer from the family was examined and showed MSS, additional screenings for endometrial cancer and gastric cancer in 3-5 year intervals should be done.
- Consensus
- Strong consensus
First-degree relatives of patients with colorectal cancer from families who fulfill the Bethesda-Criteria, but not the Amsterdam-Criteria should have colonoscopies in shorter intervals:
If no tumor tissue is available to test for HNPCC-typical characteristics, the interval should not exceed 3 years.
- Consensus
- Consent
If the tumor tissue demonstrates microsatellite stability (MSS) or a low-grade microsatellite instability (MSI-L), the interval should be 3-5 years.
- Consensus
- Consent
Background
A HNPCC-syndrome diagnosis (see section 5.2.1) should be considered in persons who are relatives of young index patients. A microsatellite analysis and/or immunohistochemical tests for mismatch repair proteins should be done. In clinical practice there are repeatedly families who have an accumulation of colorectal cancer, who do not fulfill the diagnosis criteria for HNPCC (Amsterdam II-criteria). If in these families there is no tumor tissue available or if they demonstrate a microsatellite stability (MSS), an as yet unknown hereditary gastrointestinal tumor disposition cannot be completely excluded. An examination interval of 10 years seems insufficient for this constellation, even if so far the issue has not been clarified. An interval of 3-5 years should be adequate for the familial risk.
Previously, analogous to those patients with diagnosed MSI, an annual screening was recommended for patients from families who fulfill the Amsterdam-criteria, but where a microsatellite instability was excluded. The data indicate that this is not necessary.
Intervals of 3-5 years are adequate [229][230]. Surveillance of extracolonic tumors outside the standard cancer screening procedure is not necessary for these persons.
5.1.3.2 Relatives of Patients with Colorectal Cancer
First-degree relatives of index patients with an adenoma detected before age 50, should undergo a colonoscopy at an age 10 years before the age at which the adenoma was discovered. If the initial colonoscopy did not reveal any polyps, it should be repeated at least once every 10 years. If polyps were detected, the recommendations of Chapter 6.5 apply.
- Consensus
- Strong consensus
Background
The recommendation is based on the higher risk in this population as demonstrated in section 5.1.1. [93][191][200][202].
5.2 Hereditary Colorectal Cancer
5.2.1 Risk Groups
5.2.1.1 HNPCC (Hereditary Colorectal Cancer Without Polyposis)/ Lynch-Syndrome
Risk persons for HNPCC are persons from families who fulfill the Amsterdam criteria or one of the Bethesda criteria with evidence of a microsatellite instability (MSI). This includes relatives who due to the form of inheritance could be mutation carriers.
- Consensus
- Strong consensus
Background
HNPCC-syndrome is defined according to family history criteria (Amsterdam-I- and -II- criteria, see Chapter 12.2). To identify additional persons at risk the revised Bethesda- criteria are used (Bethesda-criteria, see Chapter 12.3). The literature prefers to refer to carriers of pathogenic germline mutations in one of the MMR genes as persons with Lynch-syndrome. In contrast, the term HNPCC is often used for patients in whom no pathogenic germline mutation was identified. For reasons of simplicity only the term HNPCC is used in the following.
Mutation carriers have a very high risk of developing colorectal cancer (50-70%) or endometrial cancer (20-60%). This is also true to a lesser extent for other neoplasias such as ovarian, gastric, and small intestine as well as urothelial cancer of the renal pelvis and the ureter.
Whether a patient fulfills the Bethesda- or Amsterdam-criteria for HNPCC should be decided upon based on the family history by the treating physicians.
- Consensus
- Strong consensus
Background
In contrast to FAP, it is not easy to clinically identify HNPCC. This is because a conspicuous phenotype is lacking. For this reason, criteria have been defined which suggest to initially examine the tumor tissue and if appropriate followed by a mutation search. A diagnosis of HNPCC can be made clinically if, in the family of the patient, the so-called Amsterdam I criteria are fulfilled [231]. With HNPCC, in addition to CRC, there is an increased rate of endometrial and urothelial cancer, as well as cancer of the small intestine. The Amsterdam II criteria include these extra-colonic manifestations [175]. These criteria present a pragmatic implementation from a clinical point of view. Since nowadays many families are small, it is often not possible to fulfill these criteria. Therefore, a lack of positive family history—particularly in small families—is no argument against HNPCC. The less specific Bethesda criteria can be used to initiate a work up for possible HNPCC in smaller families and individual cases (Appendix 5.3) [232].
The general tumor risk for HNPCC carriers is given as 80 to 90%, whereby CRC is by far the most common manifestation. In the context of HNPCC the average age at CRC diagnosis is 44 years. Colorectal cancers are rarely seen before age 25. The cumulative lifetime risk of an HNPCC carrier to develop CRC is 60 to-70%. The risk for men is about 10 % higher than for women.
Endometrial cancer is the second-most common tumor in HNPCC. The lifetime risk for female carriers to develop an endometrial cancer is 40 to 60% with a median age of diagnosis between 46 and 48 years. Cancer of the ovaries occur in about 10-15% of all carriers. Stomach cancer occur in 2 to 13% of HNPCC patients and are diagnosed on average between the ages of 51 and 56. Manifestations before age 40 are rare. Most of these cancer are of the intestinal type. For Germany a cumulative lifetime risk of 6.8% up to age 70 was found [233].
The cumulative lifetime risk for small bowel cancer in the context of an HNPCC is 4-8% [233][234]. For 35-50% of the cases, HNPCC-associated small bowel cancer are localized in the duodenum [235]. Diseases before age 30 are rare. Cancer of the upper urinary tract (ureter/renal pelvis) often appear as second or third cancer. The average age of onset for these tumors is given as 50 to 63. The lifetime risk is reported as 1-12%. In some families a higher rate of urothelial cancer was observed. A recent Dutch study [236] reports a relative risk of urothelial cancer of the complete urogenital tract (including bladder cancer) of 4.2 for male and 2.2 for female carriers of pathogenic germline mutations in one of the MMR-genes compared to the general Dutch population. As yet unpublished results of the German HNPCC consortium confirms these results.
The lifetime risk for biliary tumors is higher with HNPCC, but overall relatively low. Pancreatic cancer in HNPCC patients are rare, but significantly more common than in the general population (relative risk 8.6; lifetime risk 3.7%) [237][238].
For brain tumors there is a slightly increased risk with HNPCC, histologically these are primarily astrocytomas and glioblastomas. The median age of presentation is 40 to 54 [239][240][241]. Muir-Torre syndrome is a rare phenotypic variant of HNPCC which on top of the typical HNPCC-associated tumors is associated with sebaceous gland adenomas or cancer [242].
Additional (molecular-) pathologic examinations for HNPCC should be performed if at least one revised Bethesda-criterion is fulfilled. In this case, either a quality assured immunohistochemical test of the expression of the DNA-mismatch-repair-proteins MLH1, MSH2, MSH6, and PMS2 can be performed or a test for microsatellite instability. If immunohistochemical expression of the DNA-mismatch-repair-proteins is normal, an additional microsatellite stability test should follow to definitely exclude HNPCC. This can only be omitted if the immunochemical testing definitely identified the loss of a DNA-mismatch-repair-protein.
- Consensus
- Strong consensus
Background
An algorithm to test for mismatch-repair-defects in tumor tissue is shown in Figure 3. Microsatellite instability can be demonstrated in about 80 % of the tumor tissue of patients who meet the Amsterdam I/II-criteria. These phenomena can be traced back to underlying defects in a DNA-repair enzyme which can no longer repair missing base matches during cell mitosis. These mismatches occur relatively easy in short repetitive DNA-fragments (so-called microsatellites). Accordingly, in repair-deficient HNPCC tumors a different microsatellite pattern compared to normal cells is found. This has led to the term “microsatellite instability.” Patients from families who meet the Amsterdam- criteria and whose tumor tissue shows a microsatellite stability (MSS) should, if possible, have an independent second tumor from the family tested.
In patients whose families fulfill the Bethesda criteria, microsatellite instability is found in about 30% of the patients and, thus, is a definite suggestion for the presence of HNPCC. The classical Bethesda criteria were revised in 2004 (Appendix 5.3) [243]. The sensitivity of the microsatellite analysis in HNPCC-associated tumors is 79-93 %, the immunohistochemical test (incl. MSH6 and PMS2) is comparable with a sensitivity of 94 % [244]. In comparison to microsatellite analyses (MSA), immunohistochemistry (IHC) is more cost-effective and faster. In addition, due to the malfunction of a DNA-repair protein, it gives an indication in which of the 4 known mismatch-repair-genes the disease causing germline mutation is located. If the IHC gives a definite result, the MSA can be omitted. If not, an MSA should be done.
In patients with highly microsatellite instable tumors and absence of the MLH1- protein in the immunohistochemical test, an analysis of the somatic BRAF-mutation p.Val600Glu should be performed to exclude HNPCC.
- Consensus
- Consent
Background
About 15% of sporadic CRC show HNPCC-typical alterations in the tumor tissue in terms of MSI-H and absence of the MLH1-protein in the immunohistochemical test (IHC). This is usually due to a somatic methylation of the MLH1-promotor. The methylation is associated with the somatic mutation p.Val600Glu in the BRAF-gene [245][246][247]. Therefore, for tumors with MSI-H and absence of the MLH1-protein in the IHC an additional BRAF-analysis should follow. Using this procedure it is possible to differentiate the HNPCC-associated from the sporadic CRCs, because HNPCC-associated CRCs have no BRAF-mutation. For first degree relatives of patients with sporadic MSI-H CRC the risk of developing CRC is slightly increased (standardized incidence ratio 1.60) [248]. Therefore, the screening recommendations should be done analogous to the cases with positive family history. It is possible that the risk for other tumors (stomach, ovarian) is increased for patients with BRAF-positive CRC [248].
5.2.1.2 Adenomatous Polyposis-Syndrome
5.2.1.2.1 Patients with Classic Familial Adenomatous Polyposis (FAP)
All patients with untreated FAP will - with rare exceptions - develop colorectal cancer.
- Level of evidence
- 2a
- References
- [249]
Background
Classic (typical) FAP is characterized by the presence of more than 100 colorectal adenomas. The formation of polyps generally begins in the second decade of life. Due to the large number of adenomas, the cancer risk is nearly 100%.
In addition, most patients also develop extra colonic intestinal manifestations. The most important ones are duodenal and/or papillary adenomas, which occur in about 75% of patients and are to be regarded as pre-cancerous lesions (see below). Stomach adenomas are observed much less frequently, with an incidence of <10% of patients with FAP. Glandular polyps of the stomach, which occur in at least a third of FAP patients, are not thought to have pre-neoplastic potential.
Further extra-intestinal manifestations are abdominal and extra-abdominal desmoid tumors, thyroid gland cancer, and malignant CNS tumors (mostly medulloblastomas), hepatoblastomas as well as harmless, but often diagnostically indicative osteomas, epidermoid cysts, or pigment anomalies of the retina [249].
5.2.1.2.2 Patients with Attenuated Familial Adenomatous Polyposis (AFAP)
Level of Evidence 2a
Attenuated FAP (AFAP) has to be distinguished from typical familial adenomatous polyposis. Patients with AAPC are also at a very high risk for colorectal cancer, however, polyps and cancer generally develop later, and more often in the proximal colon.
Background
In contrast to classic FAP, AFAP is typically characterized by less than 100 colorectal adenomas and/or a later occurrence of adenomas and CRC by about 10-15 years. The lifetime risk to develop CRC is also very high. Extra-colonic manifestations (e.g. desmoids) can occur [249][250][251][253][252][254]. The clinically defined AFAP is a heterogeneous group from a genetic point of view. Germline mutations in the APC-gene (5’ and 3’ end of the gene) can be detected in 15-30% of the families. The most important differential diagnosis is the MUTYH-associated polyposis (MAP) (see below) [255]. In individual cases the clinical differentiation from HNPCC can be difficult [256]. Therefore, a molecular genetic diagnosis can be very helpful (microsatellite analysis, APC, MUTYH) in the clinical differential diagnosis of some cases of attenuated FAP [257]. In the majority of patients with the clinical diagnosis AFAP, no identification of genetic mutations is possible, so it has to be assumed that additional mutations in unidentified genes exist [257].
5.2.1.2.3 Patients with MUTYH-Associated Polyposis (MAP)
MUTYH-associated polyposis (MAP) is the most important differential diagnosis of FAP. The phenotype is similar to that of AFAP; the lifetime risk for CRC is also very high for MAP. Due to the autosomal-recessive inheritance there is only a small disease risk for patients' children and heterozygous carriers. Establishing the diagnosis is usually only possible using molecular genetic tests.
Background
The autosomal-recessive hereditary MAP, which is caused by a biallele germline mutation in the MUTYH-gene, is the most important differential diagnosis of APC-associated FAP [258]. It is diagnosed in 15-20 % of the APC-mutation negative colorectal adenomatoses [259][260].
The colorectal MAP phenotype is similar to that of the AFAP: usually between 20 and several hundred adenomas occur, the mean age of diagnosis is 45 (range 12-68 years) [261]. If untreated, the CRC lifetime risk is about 70-80 % [262]. The phenotypic MAP spectrum is still not definitely known: several large population-based studies with CRC patients showed that up to one third of the biallele MUTYH-mutation carriers develop CRC without colorectal polyps [263]. In addition, it has been reported that up to 50 % of the MAP patients have hyperplastic polyps [264].
About 20% of patients have duodenal polyposis, the lifetime risk of duodenal cancer is about 4%. Overall, extraintestinal malignancy occurs significantly more often than in the standard population (odds ratio 1.9) and shows a certain overlap with HNPCC. However, there is no dominating tumor. Typical FAP-associated extraintestinal tumors such as osteoma, desmoides, and CHRPE do not occur [265].
5.2.2 Screening
5.2.2.1 HNPCC / Lynch-Syndrome
Level of Evidence: 1c (oxford 2009)
Persons at risk for HNPCC should have genetic counseling when they reach legal age (usually from 18 years of age), but before the age of 25. As soon as the disease causing mutation is known in the family, persons at risk should be made aware of the possibility of predictive testing.
Level of Evidence: 1c (oxford 2009)
If the disease causing mutation has been excluded in a person at risk, a special surveillance is no longer necessary.
- Consensus
- Strong consensus
Background
Carriers of HNPCC have mutations in so-called mismatch repair genes. To date, germ cell mutations have been demonstrated in five different genes: MSH2, MLH1, MSH6, PMS2, and EPCAM. Almost 86% of the mutations identified up to now exist in the genes MSH2 and MLH1 [266], about 10% in the MSH6 gene and 2% in the PMS2-gene. Mutations in the EPCAM-gene are found in about 2% of the families [267]. According to the GenDG, human genetic counseling must be done before the predictive genetic tests are performed. In general, a predictive test is only possible if a definite pathogenic mutation has been identified in a family member. The identification of polymorphisms or mutations with unclear pathogenic significance is not suitable for predictive genetic testing.
HNPCC-patients and persons at risk should generally undergo annual colonoscopies from the age 25.
- Consensus
- Consent
Background
HNPCC-patients have a strongly increased cancer risk. Table 6 gives an overview of the recommended cancer screening tests. Colorectal cancer occur in HNPCC patients at a median age of 44. The chance of developing this disease increases significantly from age 30. In case of very early manifestations of familial colorectal cancer, in contrast to the abovementioned recommendation, the first colonoscopy should be done 5 years before the earliest manifestation age. More than 50% of the HNPCC-associated cancer are found on the right side of the colon [240]. This is the reason a rectoscopy and/or rectosigmoidoscopy are not sufficient as a surveillance test. A prospective study showed a significant reduction in mortality as well as CRC incidence by more than 60% for both with three-year testing intervals [268]. Due to an accelerated tumor progression with interval cancer in about 4% of all patients with three-year testing intervals, an annual interval is recommended [268][269][270] (Table 6). A prospective study of the German HNPCC- consortium with 1 year intervals showed a significantly better stage distribution for detected asymptomatic CRC [229].
The stage distribution and, therefore, the prognosis of HNPCC-associated colorectal cancer that have been discovered in screening programs is significantly better than cancer which were diagnosed as a result of disease symptoms [271]. The colonoscopy may be done as a chromoendoscopy. Prospective studies demonstrated a significant increase in adenoma detection rate with the use of chromoendoscopy [272][273][274]. However, currently it is not clear whether this improves the interval cancer rate or the mortality.
For female patients with HNPCC and persons at risk, in addition to the annual gynecological exam, a transvaginal ultrasound should be performed from age 25, because of the risk of endometrial and ovarian cancer.
For female patients with HNPCC and persons at risk, in addition an endometrial biopsy should be performed from age 35.
- Consensus
- Consent
Background
These recommendations arise from the natural progression of HNPCC (see above). For female carriers, the risk of developing an endometrial cancer up to the age of 70 is 40 to 60% and for ovarian cancer about 10-15% [239][275]. Studies published so far on the efficacy of endometrial cancer screening in female patients with HNPCC clearly indicate that the transvaginal ultrasound (TVU) is not suitable as a screening-test, especially for pre- and post-menopausal women [276][277][278]. Since an endometrium biopsy using the Pipelle method in addition to TVU has been reported in the literature as the most useful alternative and since these have already been propagated in international recommendations [279], the recommendation of Overview of Guideline-Based Specific Procedural Quality Indicators of Colonoscopy from age 35 is sensible (see Table 7). For patients who no longer plan to have children, the possibility of a prophylactic hysterectomy and, if appropriate, an adnectomy should be discussed.
In addition, HNPCC-patients and persons at risk with HNPCC should have an EGD regularly from age 35.
- Consensus
- Consent
Background
HNPCC-associated gastric cancer are diagnosed at a median age of 54. They are only seen in 2% of patients before the age of 35. For Germany, a cumulative lifetime risk of 6.8 % up to age 70 was determined [233]. A familial cumulation (at least 2 affected members with gastric cancer) was only observed in 26% of the MLH1- and MSH2-mutation carriers [280]. Therefore, the EGD seems to be sensible for all mutation carriers and persons at risk from 35 years of age (see Table 6). This is also suggested, because the risk for duodenal cancer is higher than for gastric cancer, and these occur from age 30. The cumulative lifetime risk for duodenal cancer in HNPCC patients is 4-8% [233][234]. 35-50% of the small intestine cancer are located in the duodenum [235]. Due to the data available, the recommendation of the S3-guideline on gastric cancer must in the future be defined more precisely. There are no data on the issue of test intervals. In analogy to the tumor progression of colorectal cancer based on a hereditary MMR-defect, an annual interval is recommended.
Due to the increased risk of urothelial and hepatobiliary cancer, an annual upper abdominal ultrasound used to be recommended. However, its usefulness has not been confirmed and its curative potential is questionable. Therefore, it is no longer generally recommended. The benefit of the urine cytologic test has not been confirmed and has, therefore, not been generally recommended since 2004.
Background
So far, only data from one prospective randomized study exist on chemoprevention of HNPCC. The CAPP2-study tested the use of 600 mg acetylsalicylic acid and resistant starch in a 2x2 design. The primary analysis of the defined endpoints showed no significant effect of ASS [281]. After longer follow-up of 55.7 months, a significant reduction of colorectal cancer incidence (hazard ratio 0.41 (95%CI 0.19-0.86), p=0.02) as well as a non-significant reduction of other HNPCC-associated cancer (hazard ratio 0.47 (95%CI 0.21-1.06), p=0.07) was found in the subgroup of HNPCC patients who had taken 600 mg ASS for at least 2 years [282]. The study dose of 600 mg with its expected side effects seems high. The efficacy of low ASS doses for HNPCC-patients is currently not known and will be studied in a subsequent study (CAPP-3). The aim is to include as many HNPCC-patients as possible. In general, HNPCC-patients should not undergo chemoprevention with ASS until the results of this study are available.
Prophylactic colectomy or proctocolectomy in HNPCC mutation carriers shall not be performed.
A subtotal colectomy in patients with a cancer should not generally be done, but should be discussed individually with the patient.
- Consensus
- Strong consensus
After oncologic resection of a CRC in addition to the regular follow-up colonoscopy surveillance shall be performed in the same way as before surgery.
Background
Because regular surveillance can detect pre-malignant adenomas and nearly all surveillance detected cancer are UICC stage I or II [268][269] and the penetrance of the disease is not complete, prophylactic colectomies and/or proctocolectomies are not recommended. Individual constellations such as adenomas that cannot be removed endoscopically, regularly difficult colonoscopies, insufficient colonoscopy preparation despite adequate laxative procedures, and missing compliance may justify the recommendation of a prophylactic colectomy.
When cancer have been detected the patient should have an oncologic resection according to oncologic surgical standard criteria (see also Chapter 7). However, the risk of colorectal cancer in the remaining colon and the risk of extracolonic neoplasias remains increased, so that these patients require an intensive postoperative follow up. In these cases, the postoperative tumor surveillance for sporadic CRC should be combined with the HNPCC-specific screening program for CRC and extracolonic tumors. It is currently not known whether a prophylactic extended tumor resection for the prophylaxis of metachronous CRC is better than surveillance at short intervals. Previous data from retrospective case studies are insufficient. Furthermore, due to the national difference in screening intervals, they are not applicable to Germany [283][284][285][286].
For female patients who are known Lynch-syndrome mutation carriers a prophylactic hysterectomy and, if necessary, an ovarectomy at age 40 or five years before the earliest age of disease contraction in the family should be discussed.
- Consensus
- Consent
Background
This approach is based on expert opinion of the task force gynecologic oncology (AGO) of the German Cancer Society. If possible, the intervention should not be performed until after family planning has been completed. A retrospective study showed a significant reduction of endometrial and ovarian cancer incidence in these patients [287]. Following prophylactic ovarectomy, patients should take hormone replacement therapy (HRT). After a hysterectomy, HRT can be performed using only estrogens, which reduces side effects of the therapy.
5.2.2.2 Adenomatous Polyposis Syndromes
5.2.2.2.1 Patients with Classic Familial Adenomatous Polyposis (FAP)
Relatives of FAP patients who are potential mutation carriers due to the autosomal dominant inheritance are defined as persons at risk. For these persons predictive genetic testing should be recommended from age 10 after genetic counseling of the family if an APC-germline mutation has been identified in the family.
Level of Evidence: 1c (Oxford 2009)
If the mutation that was identified in the family was excluded in the person at risk (children, siblings, or parents of FAP-patients), a special surveillance is no longer necessary.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Consensus
- Strong consensus
Persons at risk for whom the mutation is confirmed or cannot be excluded should have a rectosigmoidoscopy from age 10. If there is evidence of adenomas, a complete colonoscopy must follow, and has to be repeated annually until a proctocolectomy has been performed (see below).
Background
For children or persons unable to give consent genetic consultation is done together with their legal guardians. Initiating genetic diagnostics before the age of 10 is seldom necessary, because colorectal cancer are only rarely seen among children younger than age 15 [288]. Molecular genetic testing is usually done by direct mutation testing in the APC gene. In rare cases with decisive familial constellation genetic testing may be done indirectly using coupling analyses. Definite predictive testing can only be conducted in patients when the pathogenic germline mutation has been identified in an affected family member. It always has to be combined with human genetic counseling [GenDG] [115]. A mutation is identified in about 70-80% of patients. Another method to identify gene carriers is a fundoscopic exam to identify the characteristic congenital hypertrophy of the retinal pigment epithelium (CHRPE). However,nowadays this method is used less often because of the possibility of DNA testing.
With classic FAP, polyps are always found in the rectum and sigma If rectal polyps are identified, additional proximal adenomas or even cancer can be present. In this case, a complete colonoscopy should be performed at short interval which, depending on the findings, should be repeated at least once a year. In families where genetic testing has not been performed or has not provided definite results, all persons at risk should undergo endoscopic surveillance from age 10 [189][288][289]. With specific mutations, earlier cancer manifestation in the family, or presence of symptoms, initiating screening at an even earlier age should be considered.
Level of Evidence: 1c (Oxford 2009)
Patients with classical FAP should undergo prophylactic proctocolectomy (whenever possible maintaining continence) independent of the molecular genetic testing if possible no earlier than the end of puberty.
After proctocolectomy a pouchoscopy should be performed regularly. Patients with a remaining rectal stump should untergo rectoscopies regularly. The interval depends on the test results (number, size, and histology of detected neoplasias) and should not exceed 12 months.
- Consensus
- Strong consensus
Background
The timely proctocolectomy is essential for preventing colorectal cancer [290][291][292][293][294]. The value of molecular genetic testing on therapeutic decisions is limited, because the identification of the mutation only rarely allows an individual assessment of the disease course. In a considerable proportion of patients who are clinically affected no causative mutation can be identified. The polyposis patient must be adequately treated regardless of the result of the mutation analysis. Therefore, necessary surgery should also be performed if a mutation has not been identified and, if necessary, performed before the mutation analysis has been completed [257]. The operation should generally be performed between the end of puberty and age 20. The exact time point should, however, be determined on an individual basis according to age, diagnosis, and endoscopic/histological findings (number of polyps and level of dysplasia) [293][294][295]. In the natural course of FAP, cancer appear at a median age of 36 [296]. The option of sparing the rectum should be discussed with the patient (ileorectal anastamosis, IRA). It has to be kept in mind that after a colectomy with sparing of the rectum the risk of developing a rectal stump cancer is 13% after 25 years [297]. The long-term prognosis for IPAA (ileo-pouch anal anastamosis) concerning the CRC-rate is better [298][299][300][301]. For this reason, a proctocolectomy is recommended for patients with classical FAP. The operation should be performed in an experienced center. Carrying out a proctocolectomy with a final, permanent ileostoma can in most cases nowadays be avoided.
Because several patients develop polyps in the area of the pouch next to the ileoanal anastamosis that can progress to cancer, an annual postoperative pouchoscopy is recommended. If no proctocolectomy was performed, surveillance of the rectal stump with short intervals of no more than 12 months are necessary. If new polyps are found, these should be removed.
An EGD and duodenoscopy (with side-optical view) with inspection of the papilla region should be carried out starting at age 25-30. An interval of three years is recommended if the result is negative. The interval should be shortened up to one year depending on the degree of severity of the adenoma burden (Spigelman classification).
If duodenal-/papillary adenomas are identified, an indication for endoscopic polypectomy should be considered.
If the duodenal polyposis is severe (Spigelman IV) or an invasive cancer without distant metastases is present, there is an indication for surgical resection.
- Consensus
- Consent
Background
The lifetime risk of developing duodenal polyps is between 80 and 90% for FAP patients [302][303]. Fewer than 10% of the patients develop gastric adenomas, more than 50% have fundic gland polyps of the stomach. Gastric cancer, however, do not seem to occur more often than in the general population [304]. With regard to the extent of duodenal polyposis, the Spigelman classification (see Table 7) should be used [305]. The average age of patients with serious adenomatosis of the duodenum is about 43 (range 24-65) [306]. Altogether, it appears that the growth behavior of duodenal adenomas is slower than that of colorectal adenomas [307][308] and depends more on increasing age (increases at age >40) than on the initial stage [309]. The mutation location (Codon 279- 1390) correlates with the severity of the polyposis in the duodenum, but not with the possibility that a high-grade dysplasia will develop [310][311]. The lifetime risk for a duodenal cancer for patients with FAP is between 3 and 4% [312][313] and is, therefore, up to 300 times more common than in the general population [314]. The risk that an invasive cancer is present depends on the severity of the duodenal polyposis. Thus, the risk for an invasive cancer with Spigelman II and III is 2% versus 36% for Spigelman IV [315].
The aim of an endoscopic surveillance is not the removal of all polyps, but the detection of relevant neoplasias (high-grade intraepithelial neoplasia, villous or tubolovillous adenomas). All polyps that are >1cm should be removed if technically possible. In case of smaller polyps, the larger ones should be removed and sent to pathology to determine the Spigelman score..
For FAP-patients with low-grade duodenal polyposis (Spigelman I and II ) a three year test interval seems sufficient [307]. Due to the higher risk of cancer in Spigelman stage IV, a surgical procedure is recommended. The pancreas-maintaining duodenectomy is the preferred procedure partly due to a lower morbidity rate than with a pancreatic duodenectomy [316][317]. An operative duodenotomy with polypectomy cannot be recommended due to a high rate of recurrence [318][319]. In principal, even after extensive surgical treatment the appearance of new adenomas cannot be prevented [318]. Currently, it is not clear whether regular duodenal screening prolongs life [312]. There are different approaches to handling FAP-associated papillary adenomas. Overall, there are only very few publications on the issue of FAP. Whereas some groups favor a papillectomy for every patient with any type of papillary adenoma [320][321], others prefer a monitoring strategy for small adenomas and papillectomy only in case of progression (size, histology) or development or threat of complications (e.g. cholestasis, pancreatitis) [307][308]. In summary, the following monitoring program seems sensible: Spigelman I and II: examination every 3 years; if necessary a polypectomy should be performed; Spigelman III: annual examination and, if necessary, polypectomy, Spigelman IV: surgery.
If therapy is indicated (symptoms, progression), first-line therapy of desmoids in FAP patients consists of a combination therapy using sulindac and tamoxifen. In case of progressive desmoids under this drug therapy an interdisciplinarily approach should be undertaken. Therapy options include chemotherapy, surgery, and radiotherapy.
- Consensus
- Consent
Background
Desmoid tumors appear in 10 to 30% of all patients with FAP. The risk for women to develop desmoid tumors is greater than for men. Apart from a clear genotype/phenotype correlation (APC mutation codon >1300) [322][323][324], surgical trauma can act as a trigger factor. About 50% of the desmoids appear intra-abdominally especially mesenterially and due to their local infiltrative growth often cause significant problems. For this reason, it is especially important with patients who have a positive family history or a distal APC mutation to look for the presence of desmoids before proctocolectomy and to undergo proctocolectomy as late as possible. Regular desmoid screening is not recommended if the patient has no symptoms. Desmoid screening may be done pre-operatively with suitable imaging tests. Desmoid tumors that are asymptomatic and not progressing in size often do not have to be treated. A systematic review of published clinical trials on medicinal non-cytotoxic chemotherapies demonstrates the best confirmed efficacy for treatments with sulindac (300 mg), tamoxifen (40-120 mg), or a combination therapy [325]. For raloxifen there are also comparable data from a small case series [326]. Progressive tumors under sulindac or antihormonal therapy should be treated with chemotherapy (doxorubicin and dacarbazine or methotrexat and vinblastin) or radiotherapy [327][328][329]. Results on surgical resections are controversial [330]. Especially for intra-abdominal desmoids, incomplete resections and high relapse rates are often reported [331][332][333].
For abdominal wall desmoids surgical procedures often lead to R0-resection and no recurrence [334].
In female FAP-patients, an annual ultrasound of the thyroid may be performed from age 15.
- Consensus
- Consent
Background
The lifetime risk for patients with FAP to develop thyroid cancer is 1 to 12%. About 95% of all reported thyroid cancer affect women; therefore, the risk is mainly increased in female carriers. The mean age of diagnosis is between 24 and 33 years. Manifestations before age 15 are rare [335]. Cancer often appear multifocal and sometimes bilaterally. Histologically a cribiform variant of a papillary thyroid cancer is usually present.
Two prospective [336][337] and one retrospective study [338] examined the value of a one time ultrasound screening. Benign thyroid nodules were identified in 20 to 79% of the cases. Thyroid cancer were diagnosed with a prevalence of 2.6 to 7.6%. In the largest study cancer were only detected through ultrasound and not using patient history or palpation [336]. Therefore, for female FAP-patients an annual ultrasound of the thyroid may be done from age 15. So far, there are no studies on an appropriate screening interval. The prognosis of FAP-associated thyroid cancer is good, but deaths have been reported [335][339][340]. The extent to which screening reduces mortality is unknown. The frequency of necessary adjuvant radiotherapy can possibly be reduced if more microcarcinomas are detected.
Hepatoblastomas are very rarely observed as a manifestation of FAP. Fewer than 0.5% of all children of FAP patients develop a hepatoblastoma almost exclusively before the age of 10 [341]. It seems, however, that the risk higher for boys is than for girls. In a some of the cases there was a positive family history [342]. Due to the rarity and the unclear data on whether the prognosis for hepatoblastoma patients can be improved, screening is not generally recommended [343][344].
Drug treatment of adenomas in the lower and upper gastrointestinal tract should not be generally recommended.
Background
Sulindac reduces the number of colorectal adenomas by more than 50% [345][346][347][348][349]. However, it does not prevent the formation of new polyps [350]. Furthermore, under sulindac therapy cancer were observed in the rectal stump. Sulindac is not approved in Germany. In individual cases, chemoprevention with sulindac for FAP can be used as an additive treatment after subtotal colectomy to reduce the rectal polyp burden. However, an endoscopic surveillance is mandatory.
The selective COX2-inhibitor celecoxib which leads to a reduction of rectal adenomas [351], was approved for chemoprevention of FAP as an addition to surgical procedures and endoscopic controls. Celecoxib at high doses of 400-800mg reduces the colorectal polyp number by 28% [351] and also affects duodenal polyposis [352]. However, it is not known whether its use also reduces the risk of developing cancer in these patients. COX- 2-inhibitors are associated with an increased rate of cardiovascular events [353]. The value of COX-2-inhibitors is currently unknown due to the cardiovascular side effects. Presently, they should only be used in selected cases with strict indications (risk-benefit- assessment). The drug with the ingredient celecoxib that is approved for FAP was removed from the market by the manufacturer in April 2011, because of insufficient recruitment for a post-approval study that was demanded by the European Drug Agency (EMA). In individual cases, the use of COX-2-inhibitors may be justified for selected patients to delay colectomy, after subtotal colectomy to reduce the rectum polyp burden, in patients with several duodenal polyposis and an increased surgical risk as well as an increased perforation risk or risk of bleeding with polypectomy.
5.2.2.2.2 Patients with Attenuated Familial Adenomatous Polyposis
A patient with attenuated FAP should be treated depending on age, the number of polyps, and histological findings. With endoscopically uncontrollable polyposis a colectomy is indicated. Patients who do not undergo a colectomy should have a colonoscopy once a year for the rest of their lives.
Grade of Recommendation: C
Persons at risk from families with attenuated FAP should undergo a screening colonoscopy at age 15. If no polyps are found at this point, these persons should have an annual colonoscopy starting at age 20.
Background
In patients who have an attenuated FAP, polyps occur much later and in fewer numbers than with classic FAP. The diagnosis of a CRC in adolescence has been casuistically described [354]. The polyps are often found on the right side of the colon. Hence, a complete colonoscopy must be performed for surveillance [250][251][253][254]. Because of significant variations of clinical characteristics, the decision concerning therapy must be made on an individual basis. For patients with an indication for an operation, but fewer than five rectal polyps, an ileorectal anastamosis with a remaining rectal stump is reasonable. Because extra colonic manifestations can appear as in classic FAP [355][356][357], the recommendations for classic FAP apply. It is unclear with the current amount of data available to determine up to which age surveillance of persons at risk with negative findings should be performed.
5.2.2.2.3 Patients with MUTYH-Associated Polyposis (MAP)
Testing of the MUTYH-gene shall be performed in patients who clinically have an attenuated adenomatous polyposis with no evidence of disease causing mutations in the APC-gene.
- Consensus
- Consent
Background
MUTYH-associated polyposis (MAP) is the most important differential diagnosis of FAP. The phenotype usually corresponds to the phenotype of AFAP. The lifetime risk of CRC is also very high for MAP. However, due to the autosomal-recessive germline there is only a small disease risk for a patient's children and heterozygous carriers. The diagnosis is usually only possible using molecular genetic methods. About 50% of patients already have a CRC when they are diagnosed with MAP. In one third of these patients a synchronic or metachronic CRC was observed. Polyps occur in the whole colon, CRCs are found on the right side of the colon in more than 50% of patients. The occurrence of MAP-associated CRC before age 29 is very rare.
Siblings of MAP-patients have a 25% disease risk and are considered person at risk, because of the autosomal-recessive inheritance. Predictive genetic diagnostics after human genetic counseling should be recommended to these persons from age 18- 20.
- Consensus
- Strong consensus
If both MUTYH-mutations of the index patients have been excluded, their siblings do not need to have special surveillance examinations.
- Consensus
- Strong consensus
For relatives of MAP-patients who have only one of the index patient's MUTYH- mutations (heterozygous carrier), the same screening tests are recommended as for first degree relatives of patients with sporadic CRC (see 5.1.3.1).
- Consensus
- Strong consensus
Background
To date, MAP is the only autosomal-recessively inherited disease with an increased CRC risk. It is controversial whether heterozygous carriers have an increased risk of CRC. Some recent population- and family-based studies with large collectives indicated that there is a moderately increased risk at older age (RR 1.5-2.1) [263][358][359]. First degree relatives of heterozygous carriers of MAP-patients have the highest risk for CRC (RR 2.1). The mean age of diagnosis was 70 years (range 58-82). Disease risk and time point are, thus, comparable to first degree relatives of patients with sporadic CRC.
Due to the heterozygous frequency of about 1-1.5% in the Caucasian standard population, the obligate heterozygous children of MAP patients with non-consanguine partnerships only have a slight MAP disease risk (<0.5%) [258]. If predictive testing of the child is requested to assess the disease risk, a complete mutation search must be done in the MUTYH-gene of the child or the healthy parent to identify the possible 2nd germline mutation of the healthy parent. However, the benefit of conclusive genetic results is opposed to the (rare) identification of functionally unclear genetic variants. Conclusions in individual cases on their pathogenic relevance and, thus, clinical consequences (currently) are not possible. Since the presence of a second MUTYH- mutation in children of MAP-patients cannot be completely excluded because of the expected incomplete mutation detection rates, heterozygous tested children of MAP-patients (probably) have a (likely very low) remaining risk to develop MAP. A complete colonoscopy should, thus, be considered at the age of about 30 to 40 years.
Asymptomatic biallele MUTYH-mutation carriers should have their first colonoscopy at age 18-20 years. If no polyps are found, patient monitoring should be continued.
A patient with MAP should be treated based on age, polyp number, and histologic findings. If polyposis is not endoscopically manageable, a colectomy is indicated. Patients who have not been colectomized should have lifelong annual colonoscopies.
An EGD and duodenoscopy (with side-optical view) with special inspection of the papillary region should be performed at least every three years starting from age 25- 30.
Specific surveillance examinations for extra-intestinal manifestations are not justified in MAP-patients.
A recommendation for drug treatment of adenomas in the upper and lower gastrointestinal tract cannot be given, because of missing data.
- Consensus
- Consent
Background
The colorectal phenotype of MAP is similar to the APC-associated AFAP. Polyps and CRCs usually do not become symptomatic in patients with MAP until the fourth to seventh decade of life. About 50% of patients are not diagnosed with MAP until CRC is already present, in one third of all cases a synchronical or metachronical CRC was observed [360]. The polyps occur throughout the colon, CRCs are found in over 50% of the cases in the right-hand colon, and more than 20 % in the rectosigmoid [259].Therefore, as a screening method a complete colonoscopy must be performed [250][251][253][254]. The occurrence of MAP-associated CRCs before age 29 is rare. Since the clinical manifestation varies greatly, therapy decisions should be made individually. For patients who have an indication for surgery and who have few rectal polyps, an ileorectal anastomosis leaving a rectal stump may be justifiable [361].
Although duodenal polyposis in MAP-patients is observed less often (17%) than in FAP- patients, the risk of about 4% for developing duodenal cancer seems to be comparably high [265]. In MAP duodenal cancer sometimes also occur without pre-existing duodenal adenomas [362]. It can, therefore, not be concluded at this time, whether MAP-patients should perhaps have other screening strategies than (A)FAP-patients. Overall, extra- intestinal malignomas occur significantly more often in MAP-patients than in the standard population (RR 1.9%). They show a certain overlap to HNPCC. The only systematic study in 276 patients that investigated this issue demonstrated a small to moderate, but significant increase in ovarian, bladder, and skin cancer incidence as well as a trend toward increased risk of breast cancer [265]. However, there was no dominating extra-intestinal tumor and no shift towards an earlier manifestation (median age at diagnosis of the 4 malignomas was between 51 and 61 years of age). Desmoides were not observed.
5.2.2.3 Non-Adenomatous Polyposis-Syndromes
These include especially hamartomatous polyposis-syndromes (Peutz-Jeghers- syndrome, familial juvenile polyposis, Cowden-syndrome), hyperplastic polyposis- syndrome, and hereditary mixed polyposis. Some of these diseases are very rare (their proportion of all CRCs is less than 0.1 %). Carriers have an increased risk of CRC as well as of other syndrome specific intestinal and extra-intestinal tumors (stomach, breast, etc.).
Background
In individual cases the differential diagnosis of non-adenomatous polyposis-syndromes can be very difficult and demands interdisciplinary collaboration of gastroenterologists, surgeons, pathologists, human geneticists, radiologists, and other clinical experts (especially gynecologists, urologists). The patient's diagnosis and clinical care should, therefore, be done in coordination and cooperation with centers that have experience with these syndromes [257][363]. Hamartomatous polyposis-syndromes follow autosomal-dominant inheritance. Thus, children (and if present siblings) of an affected person have a 50% risk of inheriting the underlying genetic mutation and to develop the disease in the course of their lifetime.
Peutz-Jeghers-syndrome (PJS) is an autosomal-dominant inheritable disease. It is characterized by the occurrence of hamartomatous gastrointestinal polyps and mucocutaneous melanin pigmentation which is especially visible peri-oral. The latter often fade during the course of life and are not specific. Peutz-Jeghers-polyps occur especially in the small intestines and demonstrate characteristic histology. The disease cause are germline mutations in the STK11/LKB1-gene. A mutation can be identified in more than 90% of patients who fulfill the clinical-diagnostic criteria [364]. The age of manifestation is very different. Some patients already develop symptoms in the first years of life. Complications in children include an acute abdomen caused by invaginations or an obstructive ileus as well as chronic bleeding with secondary anemia. Up to 30% of patients have had a laparotomy at the age of 10 years [365]. PJS is associated with a significantly higher risk for several intestinal and extra-intestinal tumors [368][369][370][371][372]. Aside from CRC, especially the risk for cancer of the breast, small intestine, pancreas, testicles, ovaries, and uterus is increased [374][375]. The cumulative lifetime risk for malignant tumors is reported to be about 85-90%. Overall, for tumors in the gastrointestinal tract there is a cumulative lifetime risk of 57%. The CRC-risk alone is 35-39% and is, thus, the second most frequent cancer in PJS. The lower limit of the 95% confidence interval is 30 years. The tumor risk increases quickly after age 50 [373][374][375]. The lifetime risk for gynecologic tumors is reported at 13-18% [374][375]. Ovarian tumors in PJS are usually SCTAT and of non-epithelial origin. Some are already diagnosed in small girls (mean age 28 years, range 4-57 years). Cervical cancer occur with a lifetime risk of 9% and are histologically similar to adenoma malignum in more than 75 % of the cases [374].The mean age of onset is 34 years (range 23-54 years). The risk of endometrial cancer is about 10%.
Familial juvenile polyposis (FJP) is suspected in case of a diagnosis of five or more juvenile polyps in the colon, if extracolic juvenile polyps are detected, or if juvenile polyps with corresponding positive family history are identified. The correct diagnosis of juvenile polyps can be difficult due to morphologic similarities with hyperplastic polyps as well as lymphocytic infiltrates and displastic portions: a considerable percentage of genetically confirmed cases of juvenile polyposis are initially misdiagnosed as ulcerative colitis or hyperplastic polyposis [376][377]. Therefore, in case of doubt, a second review of the histologic sample by a gastroenterologically experienced pathologist should be sought.
The disease can already become noticable in early childhood due to chronic gastrointestinal bleeding or exsudative enteropathy with concomitant delayed development. The cause is germline mutations in the SMAD4- or BMPR1A-gene. The lifetime risk for developing CRC is up to 68%. There is a clear genotype-phenotype- relationship: patients with a SMAD4-germline mutation have a higher risk of developing gastric polyps and stomach cancer as well as hereditary hemorrhagic telangiectasia (Morbus Osler-Rendu-Weber) [377][378]. In addition, the risk of pancreas cancer may be increased [379][380][381][382][382]. In case of very severe early manifesting courses juvenile polyposis of toddlers should be considered [384].
The endoscopic-histologic distinction of juvenile polyposis from the PTEN-mutation- based Cowden-syndrome or the presumably non-hereditary Cronkhite-Canada- syndrome can cause problems. It is usually done using primarily the extra-intestinal tumor spectrum and molecular genetics. Cowden-syndrome [385] is especially associated with a higher risk of breast and thyroid cancer. According to recent data, the lifetime risk for CRC also seems to be increased by 28% [386]. Furthermore, increased risks for endometrial and renal cancer as well as melanomas were reported. The Bannayan-Riley-Ruvalcaba-syndrome is viewed as a variant of the Cowden-syndrome. Both are germline mutations associated with the PTEN-gene. They are summarized under the term PTEN-hamartom-tumor-syndrome (PHTS) [387][388].
Hereditary mixed polyposis syndrome (HMPS) and hyperplastic polyposis syndrome (HPS) are difficult to define entities and there is still little known about their genetics. Both syndromes are associated with an increased - in some cases pronounced - CRC risk [389][390][391][392][393]. However, they are rare and, so far, both clinically and genetically poorly characterized. Thus, the knowledge on tumor risk is only partly conclusive. In some patients with HMPS, mutations were identified in the PTEN- or BMPR1A-genes. These cases should be viewed as (atypical) variants of the Cowden-syndrome or FJP and treated accordingly.
Due to the scarce data, general screening recommendations cannot be given. The monitoring of the patients and persons at risk should be done in cooperation with a qualified center.
- Consensus
- Consent
Background
Valid screening recommendations cannot be given, because of the scarce data available. Specific screening programs were suggested by individual experts for the more frequent syndromes. The published guideline for Peutz-Jeghers-syndrome has methological deficits and gives only little evidence for most of the recommendations [394]. Patients and persons at risk should, therefore, be monitored in close cooperation with an experienced center. For some of the syndromes, experts suggested specific age- dependent screening programs (review in [257]). However, the recommendations are contradictory and, due to the few case numbers, the efficacy of the very rare syndromes is difficult to validate.
If it can be assumed that a patient has a hereditary colon cancer or if a healthy person has a high risk of hereditary colon cancer, the patient should be referred to an interdisciplinary center with an established expertise in the field of hereditary colon cancer.
- Consensus
- Consent
Background
Monogenic-inherited colorectal cancer are rare (less than 5% of all colorectal cancer). The diagnosis has significant consequences for patients and their relatives. In case of suspicion of hereditary colorectal cancer, an experienced center for familial colon cancer or an equivalent with corresponding expertise should be contacted. A molecular genetic diagnosis of affected patients serves to confirm the diagnosis and makes it possible to conduct predictive testing of family members. A relevant germ cell mutation test should be conducted following the guidelines for diagnosis of the genetic disposition for cancer diseases of the Federal Physician’s Association and the genetic diagnostics regulations (GenDG) [115]. As an example, the algorithm for the HNPCC-/Lynch-syndrome is shown in Figure 2. Analogously, it is valid for the other hereditary syndromes with increased colon cancer risk. All patients and persons with higher risk in these groups have, in addition to an increased risk for colorectal cancer, an increased risk for extracolonic neoplasias. Due to the usually autosomal-dominant inheritance process, first-degree relatives of index patients have a 50% risk of having inherited this genetic predisposition. A predictive genetic test according to the GenDG always has to be preceded by genetic counseling of the patient concerned and can only take place if a clear pathogenic germ cell mutation has been identified in an affected family member (see Fig. 2) [115].
The possibility and benefit of psychosocial counseling and care should be pointed out to already affected persons, index patients, and persons at risk for monogenous hereditary disease who have an increased risk for colorectal cancer.
- Consensus
- Strong consensus
Background
In patients and their family the diagnosis of manifested hereditary tumor syndromes, the knowledge of a highly increased disease risk, or the definite detection of a mutation may be accompanied by numerous psychosocial stress factors. Corresponding studies were done in particular for FAP. These included not only adults and adolescents, but also children and their parents [302][303][306]. Relevant stressors included altered physical perception, fear of surgical interventions, screening tests, and future tumor progression, fear of occupational limitations, communication of the illness to the social environment, insecurity about having children, as well as coming to terms with family members who died early of cancer and corresponding conflict within the family.
Predictive testing of under age persons is also associated with special challenges. These include an inability of these persons to decide for themselves and their limited understanding of the meaning and consequences of the testing. In addition to clinical and human genetic counseling, psychosocial patient counseling can help patients and persons at risk in making their decision for or against having genetic diagnostics and coming to terms with the test results.
5.3 Chronic Inflammatory Bowel Diseases
5.3.1 Colitis Ulcerosa
For patients with ulcerative colitis, the risk of CRC is increased in comparison to the standard population. Specific recommendations are given in the S3-Guideline on Diagnostics and Therapy of Ulcerative Colitis.
- Consensus
- Strong consensus
Monitoring Colonoscopy, Time Strategy (excerpt from the S3-LL CU [395])
Since the colitis-associated colon cancer mortality can be decreased by using endoscopic screening, regular monitoring colonoscopies should be performed.
To determine a monitoring strategy, a control colonoscopy should be performed in all UC-patients no longer than 8 years after symptoms have started. This should be done regardless of the disease activity to assess the disease extent.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 4
- Consensus
- Consent
- References
- [398]
Monitoring colonoscopies should be performed every 1-2 years for extensive UC from the 8th year or for distal UC from the 15th year after initial manifestation.
If PSC is simultaneously present, the monitoring colonoscopies should be performed annually regardless of the disease activity and extent of UC starting from the time PSC was diagnosed.
After subtotal colectomy, in analogy the same endoscopic monitoring strategy as for UC without resection should be followed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 4
- Consensus
- Strong consensus
- References
- [402]
Comment
A meta-analysis by Collins from the year 2006 summarizes the direct and indirect evidence on monitoring colonoscopies for ulcerative colitis. The three identified case control studies did not show a statistically significant colon cancer risk reduction. It should be noted that, from a present day perspective, these were small studies with partially inadequate colonoscopy standards. In contrast, the meta-analysis gave clear from indirect evidence that monitoring colonoscopies very likely reduce the risk of dying of a colitis-associated colon cancer [396]. At the same time they are cost effective. This is based on the fact that colitis-associated colon cancer are detected earlier even if they can arise between monitoring intervals [397]. The cancer risk increases with the duration of disease and its extent. This is the reason that patients with pancolitis should begin regular monitoring earlier than patients with distal colitis. An initially distal colitis inflammation can develop into a pancolotis without clinical evidence. Therefore, a screening colonoscopy should be done within 8 years after the first disease symptoms appeared to check the extent and then to decide on a monitoring strategy. A Dutch study indicates that already up to 22% of patients have developed colitis-associated colon cancer before starting the monitoring colonoscopies recommended so far [403]. If patients with PSC were excluded (who should be monitored from the time of diagnosis), the rate of "missed" cancer was reduced to about 15%.
The screening interval should not exceed 2 years, because interval cancer can already arise in this period [398][399]. Since for proctitis the risk is only minimally increased at most - if other risk factors are not present - regular surveillance is not necessary. Monitoring of patients with CU and PSC from the time of diagnosis should be done annually independent of its extent, because the cancer risk is increased 5-fold [401] and because cancer arise more frequently on the right side [400].
After subtotal colectomy, cancer can occur in the remaining colon, as well as after restorative proctocolectomy in the pouch or depending on the operation technique in the area of the remaining colon mucosa distal to the anastomosis [402]. Therefore, a regular surveillance of the remaining colon or pouch is recommended.
5.3.2 Crohn's Disease
CRC risk in patients with Crohn's disease seems to be higher than in the general population especially if the colon is affected. The benefit of screening programs with ileocolonscopies to screen for cancer in Crohn colitis is unknown. The data are discussed in the S3-Guideline on Diagnostics and Therapy of Crohn's Disease [404].
5.4 Appendix: Figures and Tables of TK III
5.4.1 Algorithmus: Genetic diagnostics and screening
* A diagnostic germline exam requires informed consent and documentation of contents of the consultation by the initiating physician according to the GenDG . Alternatively, a genetic consultation may be performed. The results must be communicated in a genetic consultation according to the GenDG.
** Predictive genetic germline diagnostics for asymptomatic individuals can only be performed after a genetic consultation according to the GenDG. The results must also be communicated in a genetic consultation according to GenDG.
# For high grade suspicion of HNPCC/Lynch-syndrome (e.g. positive Amsterdam-criteria) and absence of tumor tissue, a direct mutation analysis may be performed.
## If the patient does not wish to have germline diagnostics, a HNPCC-screening should nonetheless be recommended.
Figure 1: Algorithm on Genetic Diagnostic Procedures in Patients with Hereditary Tumor Disposition Syndrome Using HNPCC-/Lynch-Syndrome as an Example. To identify MSI if HNPCC-/Lynch-syndrome is suspected, please see Figure 2
5.4.2 Diagnostic algorithm immunohistochemistry / MSI for work up of mismatch-repair-defect
* >10% of tumor cells are nucleus positive in each; ** in <10% of tumor cells are nucleus positive
Figure 2: Algorithm on the Molecular Pathologic Differential Diagnosis Procedures of Mismatch-Repair-Defects if HNPCC-/Lynch-syndrome is Suspected. Please see Figure 1 for possible subsequent genetic diagnostics.
5.4.3 Recommended Screening Programs for HNPCC
Table 3: Recommended Screening Programs for HNPCC
| Age | Examination | Interval |
| From age 25 | Physical exam | annually |
| Colonoscopy | annually | |
| Gynecologic exam incl. transvaginal sonography (in women) | annually | |
| From age 35 | EGD | regularly |
| Endometrial biopsy (in women) | regularly |
5.4.4 Spigelman-Classification
Table 4: Classification Duodenal Polyposis Characteristics According to the Spigelman- Classification (modified according to [309])
| Number of points | |||
| 1 | 2 | 3 | |
| Number of polyps | 1-4 | 5-20 | >20 |
| Polyp size (mm) | 1-4 | 5-10 | >10 |
| Histology | tubular | tubular villous | villous |
| Intra-epithelial neoplasia | low grade | - | high grade |
|
Stage 0: 0 points Stage I: 1-4 points Stage II: 5-6 points Stage III: 7-8 points Stage IV: 9-12 points |
|||
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